6ty5
Crystal structure of human TLR8 in complex with Compound 11Crystal structure of human TLR8 in complex with Compound 11
Structural highlights
FunctionTLR8_HUMAN Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.[1] Publication Abstract from PubMedInappropriate activation of endosomal TLR7 and TLR8 occurs in several autoimmune diseases, in particular systemic lupus erythematosus (SLE). Herein, the development of a TLR8 antagonist competition assay and its application for hit generation of dual TLR7/8 antagonists are reported. The structure-guided optimization of the pyridone hit 3 using this biochemical assay in combination with cellular and TLR8 cocrystal structural data resulted in the identification of a highly potent and selective TLR7/8 antagonist (27) with in vivo efficacy. The two key steps for optimization were (i) a core morph guided by a TLR7 sequence alignment to achieve a dual TLR7/8 antagonism profile and (ii) introduction of a fluorine in the piperidine ring to reduce its basicity, resulting in attractive oral pharmacokinetic (PK) properties and improved TLR8 binding affinity. Target-Based Identification and Optimization of 5-Indazol-5-yl Pyridones as Toll-like Receptor 7 and 8 Antagonists Using a Biochemical TLR8 Antagonist Competition Assay.,Knoepfel T, Nimsgern P, Jacquier S, Bourrel M, Vangrevelinghe E, Glatthar R, Behnke D, Alper PB, Michellys PY, Deane J, Junt T, Zipfel G, Limonta S, Hawtin S, Andre C, Boulay T, Loetscher P, Faller M, Blank J, Feifel R, Betschart C J Med Chem. 2020 Aug 13;63(15):8276-8295. doi: 10.1021/acs.jmedchem.0c00130. Epub, 2020 Jul 30. PMID:32786235[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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